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This article is about the clotting of blood. For other uses, see Coagulation (disambiguation).

Coagulation is a complex process by which blood forms clots. Blood is a specialized Bodily fluid that delivers necessary substances to the body's cells such as nutrients and oxygen—and transports Waste products A thrombus, or blood clot, is the final product of the Blood coagulation step in Hemostasis. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet and fibrin containing clot to stop bleeding and begin repair of the damaged vessel. Hemostasis (or Haemostasis refers to a process whereby bleeding is halted in most animals with a closed Circulatory system. The blood vessels are part of the Circulatory system and function to transport Blood throughout the body Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood Bleeding, technically known as hemorrhaging / haemorrhaging (see American and British spelling differences) is the loss of Blood from Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) and/or clotting (thrombosis). Bleeding, technically known as hemorrhaging / haemorrhaging (see American and British spelling differences) is the loss of Blood from Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory

Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. Conservation refers to a high degree of similarity in orthologous DNA sequences protein sequences, or Protein structures amongst various Mammals ( class Mammalia) are a class of Vertebrate Animals characterized by the presence of Sweat glands, including sweat glands The system in humans has been the most extensively researched and therefore is the best understood.

Coagulation is initiated almost instantly after an injury to the blood vessel damages the endothelium (lining of the vessel). The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the Platelets immediately form a hemostatic plug at the site of injury; this is called primary hemostasis. Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved Secondary hemostasis occurs simultaneously; proteins in the blood plasma, called coagulation factors, respond in a complex cascade to form fibrin strands which strengthen the platelet plug. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Blood plasma is the Liquid component of Blood, in which the Blood cells are suspended Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood [1]

Contents

Physiology

Platelet activation

Damage to blood vessel walls exposes subendothelium proteins, most notably collagen, present under the endothelium. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the Circulating platelets bind collagen with surface collagen-specific glycoprotein Ia/IIa receptors. Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached The adhesion is strengthened further by the large, multimeric circulating proteins von Willebrand factor (vWF), which forms links between the platelets glycoprotein Ib/IX/V and the collagen fibrils. Von Willebrand factor (vWF is a Blood Glycoprotein involved in Hemostasis. This adhesion activates the platelets.

Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP, serotonin, platelet activating factor (PAF), vWF, platelet factor 4 and thromboxane A2 (TXA2) which in turn activate additional platelets. Adenosine diphosphate, abbreviated ADP, is a Nucleotide. It is an Ester of Pyrophosphoric acid with the Nucleoside Adenosine Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine is a potent Phospholipid activator Von Willebrand factor (vWF is a Blood Glycoprotein involved in Hemostasis. Platelet factor 4 (PF4 is a small Cytokine belonging to the CXC Chemokine family that is also known as chemokine (C-X-C motif ligand 4 (CXCL4. Thromboxane A2 is a Thromboxane. It is generated from Prostaglandin H2 by Thromboxane-A synthase. The granules contents activate a Gq-linked protein receptor cascade resulting in increased calcium concentration in the platelets' cytosol. G protein-coupled receptors ( GPCRs) also known as seven transmembrane domain receptors, 7TM receptors, heptahelical receptors, and The calcium activates protein kinase C which in turn activates phospholipase A2 (PLA2). Protein kinase C ('PKC') is a family of protein kinases consisting of ~10 Isozymes. Phospholipases A2 (PLA2s are upstream regulators of many inflammatory processes PLA2 then modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen. Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. The activated platelets changed shape from spherical to stellate and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets.

The coagulation cascade

The coagulation cascade.
The coagulation cascade.

The coagulation cascade of secondary hemostasis has two pathways, the contact activation pathway (formerly known as the intrinsic pathway) and the tissue factor pathway (formerly known as the extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. A zymogen (or proenzyme) is an inactive Enzyme precursor. A zymogen requires a biochemical change (such as a Hydrolysis reaction revealing the Serine proteases or serine endopeptidases (newer name are Proteases ( Enzymes that cut Peptide bonds in Proteins in which one of Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form. Roman numerals are a Numeral system originating in ancient Rome, adapted from Etruscan numerals.

The coagulation factors are generally serine proteases (enzymes). Serine proteases or serine endopeptidases (newer name are Proteases ( Enzymes that cut Peptide bonds in Proteins in which one of Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins There are some exceptions. For example, FVIII and FV are glycoproteins and Factor XIII is a transglutaminase. Transglutaminases are a family of Enzymes ( that Catalyze the formation of a Covalent bond between a free amine group (e Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as inactive zymogens. A zymogen (or proenzyme) is an inactive Enzyme precursor. A zymogen requires a biochemical change (such as a Hydrolysis reaction revealing the

The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.

Tissue factor pathway

The main role of the tissue factor pathway is to generate a "thrombin burst", a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously. Thrombin (activated Factor II ') is a Coagulation protein that has many effects in the coagulation cascade. FVIIa circulates in a higher amount than any other activated coagulation factor.

Contact activation pathway

The contact activation pathway begins with formation of the primary complex on collagen by high-molecular weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor). Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein High-molecular-weight kininogen ( HMWK) also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor or the HMWK-kallikrein factor Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family Prekallikrein is converted to kallikrein and FXII becomes FXIIa. Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The tenase complex is formed by the activated forms of the blood Coagulation factors Factor VIII and Factor IX. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family

Final common pathway

Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers. Protein C is a major physiological Anticoagulant. It is a Vitamin K -dependent Serine protease Enzyme ( that is activated by Thrombin Thrombomodulin, CD 141 or BDCA-3 is an Integral membrane protein expressed on the surface of endothelial cells

Following activation by the contact factor or tissue factor pathways the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways. The tenase complex is formed by the activated forms of the blood Coagulation factors Factor VIII and Factor IX.

Cofactors

Various substances are required for the proper functioning of the coagulation cascade:

Regulators

Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis:

Fibrinolysis

Main article: Fibrinolysis

Eventually, all blood clots are reorganised and resorbed by a process termed fibrinolysis. Fibrinolysis is the process wherein a Fibrin clot, the product of Coagulation, is broken down Fibrinolysis is the process wherein a Fibrin clot, the product of Coagulation, is broken down The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors. Plasmin is an important Enzyme ( present in Blood that degrades many Blood plasma proteins most notable Fibrin clots The degradation

Testing of coagulation

Numerous tests are used to assess the function of the coagulation system:

The contact factor pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test. The partial thromboplastin time' (PTT or activated partial thromboplastin time ( aPTT or APTT) is a performance indicator measuring the efficacy of both the "intrinsic"

The tissue factor pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. Tissue factor, also called thromboplastin, factor III or CD142 is a Protein present in subendothelial tissue, Platelets The prothrombin time ( PT) and its derived measures of prothrombin ratio ( PR) and international normalized ratio ( INR) are measures PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin. The prothrombin time ( PT) and its derived measures of prothrombin ratio ( PR) and international normalized ratio ( INR) are measures Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an Anticoagulant.

The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). The Thrombin Clotting Time (TCT also known as the Thrombin Time (TT is a coagulation assay which is usually performed in order to detect for the therapeutic level of the Anticoagulant Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot.

If a coagulation factor is part of the contact or tissue factor pathway, a deficiency of that factor will affect only one of the tests: thus hemophilia A, a deficiency of factor VIII, which is part of the contact factor pathway, results in an abnormally prolonged aPTT test but a normal PT test. Haemophilia A (also spelled Hemophilia A or Hæmophilia A) is a Blood clotting disorder caused by a mutation of the Factor VIII gene The exceptions are prothrombin, fibrinogen and some variants of FX which can only be detected by either aPTT or PT. If an abnormal PT or aPTT is present additional testing will occur to determine which (if any) factor is present as aberrant concentrations.

Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.

Role in disease

Problems with coagulation may dispose to hemorrhage, thrombosis, and occasionally both, depending on the nature of the pathology.

Platelet disorders

Platelet conditions may be inborn or acquired. Some inborn platelet pathologies are Glanzmann's thrombasthenia, Bernard-Soulier syndrome (abnormal glycoprotein Ib-IX-V complex), gray platelet syndrome (deficient alpha granules) and delta storage pool deficiency (deficient dense granules). Glanzmann's thrombasthenia is an extremely rare disorder of the Blood, in which the Platelets lack Glycoprotein IIb/IIIa. Bernard-Soulier syndrome (BSS also called hemorrhagiparous thrombocytic dystrophy, is an Autosomal recessive bleeding disorder that causes a deficiency Gray platelet syndrome, or platelet alpha-granule deficiency, is a rare congenital bleeding disorder caused by a reduction or absence of the Platelet alpha-granules In Platelets, the term "alpha granules" is used to describe granules containing several growth factors (such as Insulin-like growth factor 1, Platelet-derived Hermansky-Pudlak syndrome (HPS is a rare Autosomal Recessive disorder which results in oculocutaneous albinism (decreased Pigmentation) bleeding Dense granules (also known as dense bodies or delta granules) are specialized secretory Organelles They contain adenine nucleotides (ADP and Most are rare conditions. Most inborn platelet pathologies predispose to hemorrhage. von Willebrand disease is due to deficiency or abnormal function of von Willebrand factor, and leads to a similar bleeding pattern; its milder forms are relatively common. Von Willebrand disease (vWD is the most common hereditary Coagulation abnormality described in humans although it can also be acquired as a result of other medical conditions Von Willebrand factor (vWF is a Blood Glycoprotein involved in Hemostasis.

Decreased platelet numbers may be due to various causes, including insufficient production (e. g. in myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system (immune thrombocytopenic purpura/ITP), and consumption due to various causes (thrombotic thrombocytopenic purpura/TTP, hemolytic-uremic syndrome/HUS, paroxysmal nocturnal hemoglobinuria/PNH, disseminated intravascular coagulation/DIC, heparin-induced thrombocytopenia/HIT). The myelodysplastic syndromes (MDS formerly known as "preleukemia" are a diverse collection of hematological conditions united by ineffective production (or Idiopathic thrombocytopenic purpura (ITP is the condition of having a low Platelet count ( Thrombocytopenia) of no known cause ( Idiopathic) Thrombotic thrombocytopenic purpura ( TTP or Moschcowitz disease) is a rare disorder of the blood-coagulation system causing extensive microscopic In Medicine, hemolytic-uremic syndrome (or haemolytic-uraemic syndrome, abbreviated HUS is a disease characterized by Microangiopathic hemolytic anemia Paroxysmal nocturnal hemoglobinuria (PNH sometimes referred to as Marchiafava-Micheli syndrome, is a rare acquired potentially life-threatening disease of the blood characterised Disseminated intravascular coagulation ( DIC) also known as consumptive coagulopathy, is a pathological activation of Coagulation (blood clotting mechanisms Heparin-induced thrombocytopenia (HIT with or without thrombosis (HITT is Thrombocytopenia (low Platelet counts due to the administration of Heparin Most consumptive conditions lead to platelet activation, and some are associated with thrombosis.

Disease and clinical significance of thrombosis

The best-known coagulation factor disorders are the hemophilias. Haemophilia (also spelled as hemophilia The three main forms are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency). Haemophilia A (also spelled Hemophilia A or Hæmophilia A) is a Blood clotting disorder caused by a mutation of the Factor VIII gene Haemophilia B (also spelled Hemophilia B or Hæmophilia B) is a blood clotting disorder caused by a Mutation of the Factor IX Haemophilia C is a mild form of Haemophilia affecting both sexes Hemophilia A and B are X-linked recessive disorders whereas Hemophilia C is much more rare autosomal dominant disorder most commonly seen in Ashkenazi Jews. Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim ( Hebrew: אַשְׁכֲּנָזִים, ˌaʃkəˈnazim sing

von Willebrand disease (which behaves more like a platelet disorder except in severe cases), is the most common hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant. Von Willebrand disease (vWD is the most common hereditary Coagulation abnormality described in humans although it can also be acquired as a result of other medical conditions In this disease there is a defect in von Willebrand factor (vWF) which mediates the binding of glycoprotein Ib (GPIb) to collagen. This binding helps mediate the activation of platelets and formation of primary hemostasis.

Bernard-Soulier syndrome there is a defect or deficiency in GPIb. GPIb, the receptor for vWF, can be defective and lead to lack of primary clot formation (primary hemostasis) and increased bleeding tendency. This is an autosomal recessive inherited disorder.

Thrombasthenia of Glanzman and Naegeli (Glanzmann thrombasthenia) is extremely rare. Glanzmann's thrombasthenia is an extremely rare disorder of the Blood, in which the Platelets lack Glycoprotein IIb/IIIa. It is characterized by a defect in GPIIb/IIIa fibrinogen receptor complex. When GPIIb/IIIa receptor is dysfunctional fibrinogen cannot cross-link platelets which inhibits primary hemostasis. This is an autosomal recessive inherited disorder. In liver failure (acute and chronic forms) there is insufficient production of coagulation factors by the liver; this may increase bleeding risk. Liver failure is the inability of the Liver to perform its normal synthetic and metabolic function as part of normal physiology

Deficiency of Vitamin K may also contribute to bleeding disorders because clotting factor maturation depends on Vitamin K.

Thrombosis is the pathological development of blood clots. Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory These clots may break free and become mobile forming an embolus or grow to such a size that occludes the vessel in which it developed. In Medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the Body (through circulation An embolism is said to occur when the thrombus (blood clot) becomes a mobile embolus and migrates to another part of the body, interfering with blood circulation and hence impairing organ function downstream of the occlusion. In Medicine, an embolism occurs when an object (the embolus, plural emboli) migrates from one part of the Body (through circulation A thrombus, or blood clot, is the final product of the Blood coagulation step in Hemostasis. This causes ischemia and often leasds to ischemic necrosis of tissue. In Medicine, ischemia ( Greek ισχαιμία, isch- is restriction hema or haema is Blood) is a restriction Necrosis (in Greek Νεκρός = "dead" is the name given to unnatural Death of cells and living tissue. Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity, economy class syndrome), but a small proportion of people harbor predisposing conditions known collectively as thrombophilia (e. Surgery (from the χειρουργική cheirourgikē, via chirurgiae meaning "hand work" is a medical specialty that uses operative manual and instrumental Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled Obesity is a condition in which excess Body fat has accumulated to such an extent that health may be negatively affected Economy class syndrome is the occurrence of Deep vein thrombosis in air travelers g. antiphospholipid syndrome, factor V Leiden and various other rarer genetic disorders). Antiphospholipid syndrome (APS or APLS or antiphospholipid antibody syndrome is a disorder of Coagulation, which causes blood clots ( Thrombosis) in both Factor V Leiden (sometimes Factor VLeiden) is the name given to a variant of human Factor V that causes a hypercoagulability disorder

Mutations in factor XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency towards thrombophlebitis. Hageman factor is a plasma protein now usually known as factor XII. Thrombophlebitis is Phlebitis (vein Inflammation) related to a blood clot or Thrombus. Other mutations have been linked with a rare form of hereditary angioedema (type III). Angioedema ( BE: angiooedema) also known by its Eponym Quincke's edema, is the rapid swelling ( Edema) of the Dermis

Pharmacology

Procoagulants

The use of adsorbent chemicals, such as zeolites, and other hemostatic agents is also being explored for use in sealing severe injuries quickly. Zeolites (Greek zein, "to boil" lithos, "a stone" are hydrated Aluminosilicate Minerals and have a micro-porous structure An antihemorrhagic ( antihaemorrhagic) agent is a substance that promotes Hemostasis (stops Bleeding) Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms.

Desmopressin is used to improve platelet function by activating arginine vasopressin receptor 1A. Desmopressin (trade names DDAVP, Stimate, Minirin) is a Synthetic replacement for antidiuretic hormone, the Hormone that Arginine vasopressin receptor 1A (AVPR1A is a Protein that acts as receptor for arginine vasopressin.

Coagulation factor concentrates are used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. Haemophilia (also spelled as hemophilia Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma are commonly-used coagulation factor products. Prothrombin Complex Concentrate (PCC is a combination of blood Clotting factors II VII IX and X Cryoprecipitate, also called "Cryoprecipitated Antihemophilic Factor" "Cryoprecipitated AHF" and most commonly just "cryo" is a frozen blood product prepared Fresh Frozen Plasma ( FFP) is defined as the fluid portion of one unit of Human blood that has been centrifuged separated and frozen solid at -18° C (or colder Recombinant activated human factor VII is are increasingly popular in the treatment of major bleeding. Factor VII (formerly known as proconvertin) is one of the central Proteins in the coagulation cascade.

Tranexamic acid and aminocaproic acid inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. Tranexamic acid (commonly marketed as Cyklokapron in the US and as Transamin in Asia is often prescribed for excessive bleeding Aminocaproic acid (also known as Amicar є-amino caproic acid or 6-aminohexanoic acid is a derivative and analogue of the Amino acid Lysine, which makes it an effective Before its withdrawal, aprotinin was used in some forms of major surgery to decrease bleeding risk and need for blood products. Aprotinin, also known as bovine pancreatic trypsin inhibitor BPTI (Trasylol Bayer) is a protein that is used as Medication administered by injection

Anticoagulants

Main articles: Antiplatelet drug and Anticoagulant

Anticoagulants and anti-platelet agents are amongst the most commonly used medicines. An antiplatelet drug is a member of a class of pharmaceuticals that decreases Platelet aggregation and inhibits Thrombus formation An anticoagulant is a substance that prevents coagulation; that is it stops Blood from clotting Anti-platelet agents include aspirin, clopidogrel, dipyridamole and ticlopidine; the parenteral glycoprotein IIb/IIIa inhibitors are used during angioplasty. An antiplatelet drug is a member of a class of pharmaceuticals that decreases Platelet aggregation and inhibits Thrombus formation Aspirin, or acetylsalicylic acid (ASA (əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd is a Salicylate drug, often used as an Analgesic to relieve Clopidogrel is a potent oral antiplatelet agent often used in the treatment of Coronary artery disease, Peripheral vascular disease, and Cerebrovascular Dipyridamole is a drug that inhibits thrombus formation when given chronically and causes Vasodilation when given at high doses over short time Ticlopidine (trade name Ticlid) is an Antiplatelet drug in the Thienopyridine family In Medicine, glycoprotein IIb/IIIa inhibitors, also GpIIb/IIIa inhibitors, is a class of Antiplatelet agents Several GpIIb/IIIa inhibitors exist Angioplasty is the technique of mechanically widening a narrowed or totally obstructed Blood vessel; typically as a result of Atherosclerosis.

Of the anticoagulants, warfarin (and related coumarins) and heparin are the most commonly used. Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an Anticoagulant. Coumarin is a Chemical compound ( Benzopyrone) a Toxin found in many Plants notably in high concentration in the Tonka bean, Heparin, a highly-sulfated Glycosaminoglycan, is widely used as an injectable Anticoagulant and has the highest negative Charge density of any known Warfarin interacts with vitamin K, while heparin and related compounds increase the action of antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is under development; some members are already in clinical use (such as lepirudin). Direct thrombin inhibitors (DTIs are a class of Medication that act as Anticoagulants (delaying blood clotting) by directly inhibiting the Enzyme Lepirudin ( Refludan) is an Anticoagulant which functions as a Direct thrombin inhibitor. Also under development are other small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e. g. rivaroxaban). Rivaroxaban (BAY 59-7939 is an oral Anticoagulant under development by Bayer; it will be marketed as Xarelto.

Coagulation factors

Coagulation factors and related substances
Number and/or name Function
I (fibrinogen) Forms clot (fibrin)
II (prothrombin) Its active form (IIa) activates I, V, VIII, XI, XIII, protein C, platelets
Tissue factor Co-factor of VIIa (formerly known as factor III)
Calcium Required for coagulation factors to bind to phospholipid (formerly known as factor IV)
V (proaccelerin, labile factor) Co-factor of X with which it forms the prothrombinase complex
VI Unassigned – old name of Factor Va
VII (stable factor) Activates IX, X
VIII (antihemophilic factor) Co-factor of IX with which it forms the tenase complex
IX (Christmas factor) Activates X: forms tenase complex with factor VIII
X (Stuart-Prower factor) Activates II: forms prothrombinase complex with factor V
XI (plasma thromboplastin antecedent) Activates IX
XII (Hageman factor) Activates factor XI and prekallikrein
XIII (fibrin-stabilizing factor) Crosslinks fibrin
von Willebrand factor Binds to VIII, mediates platelet adhesion
prekallikrein Activates XII and prekallikrein; cleaves HMWK
high molecular weight kininogen (HMWK) Supports reciprocal activation of XII, XI, and prekallikrein
fibronectin Mediates cell adhesion
antithrombin III Inhibits IIa, Xa, and other proteases;
heparin cofactor II Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")
protein C Inactivates Va and VIIIa
protein S Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein)
protein Z Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI
Protein Z-related protease inhibitor (ZPI) Degrades factors X (in presence of protein Z) and XI (independently)
plasminogen Converts to plasmin, lyses fibrin and other proteins
alpha 2-antiplasmin Inhibits plasmin
tissue plasminogen activator (tPA) Activates plasminogen
urokinase Activates plasminogen
plasminogen activator inhibitor-1 (PAI1) Inactivates tPA & urokinase (endothelial PAI)
plasminogen activator inhibitor-2 (PAI2) Inactivates tPA & urokinase (placental PAI)
cancer procoagulant Pathological factor X activator linked to thrombosis in cancer

History

Initial discoveries

Theories on the coagulation of blood have existed since antiquity. Fibrin (also called Factor Ia) is a Protein involved in the clotting of blood Thrombin (activated Factor II ') is a Coagulation protein that has many effects in the coagulation cascade. Tissue factor, also called thromboplastin, factor III or CD142 is a Protein present in subendothelial tissue, Platelets Calcium (ˈkælsiəm is the Chemical element with the symbol Ca and Atomic number 20 Factor V is a Protein of the Coagulation system rarely referred to as proaccelerin or labile factor. The prothrombinase complex consists of the serine protease Factor Xa, and the protein cofactor Factor Va The complex assembles on negatively charged phospholipid Factor VII (formerly known as proconvertin) is one of the central Proteins in the coagulation cascade. Factor VIII (FVIII is an essential Clotting factor A deficiency of FVIII causes Hemophilia A, a bleeding disorder The tenase complex is formed by the activated forms of the blood Coagulation factors Factor VIII and Factor IX. Factor IX (or Christmas factor) is one of the Serine proteases ( of the Coagulation system it belongs to peptidase family S1 The tenase complex is formed by the activated forms of the blood Coagulation factors Factor VIII and Factor IX. Factor X, also known by the Eponym Stuart-Prower factor or as thrombokinase, is an Enzyme ( of the coagulation cascade. The prothrombinase complex consists of the serine protease Factor Xa, and the protein cofactor Factor Va The complex assembles on negatively charged phospholipid Factor XI or plasma thromboplastin antecedent is one of the Enzymes of the coagulation cascade. Hageman factor is a plasma protein now usually known as factor XII. Factor XIII or fibrin stabilizing factor is an Enzyme ( of the blood coagulation system that crosslinks Fibrin. Von Willebrand factor (vWF is a Blood Glycoprotein involved in Hemostasis. Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family High-molecular-weight kininogen ( HMWK) also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor or the HMWK-kallikrein factor Fibronectin is a high-molecular-weight extracellular matrix Glycoprotein containing about 5% Carbohydrate that binds to membrane spanning Receptor proteins Antithrombin (AT is a small protein molecule that inactivates several enzymes of the Coagulation system Heparin cofactor II, a protein encoded by the SERPIND1 gene is a Coagulation factor that inhibits IIa and is a cofactor for Heparin and Dermatan Dermatan sulfate is a Glycosaminoglycan (formerly called a mucopolysaccharide found mostly in Skin, but also in Blood vessels, Heart valves, Protein C is a major physiological Anticoagulant. It is a Vitamin K -dependent Serine protease Enzyme ( that is activated by Thrombin Protein S is a Vitamin K -dependent plasma Glycoprotein synthesized in the liver Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of Blood clots It is Vitamin K -dependent and Plasmin is an important Enzyme ( present in Blood that degrades many Blood plasma proteins most notable Fibrin clots The degradation Alpha 2-antiplasmin (or α2-antiplasmin or plasmin inhibitor) is a Serine protease inhibitor (serpin responsible for inactivating Plasmin Tissue plasminogen activator (abbreviated tPA or PLAT) is a Protein involved in the breakdown of Blood clots Specifically it is a Urokinase (Abbokinase also called urokinase-type Plasminogen Activator (uPA is a Serine protease ( Plasminogen activator inhibitor-1 is the principal inhibitor of Tissue plasminogen activator (tPA and Urokinase (uPA the activators of Plasminogen Plasminogen activator inhibitor-2 (placental PAI is a Coagulation factor that inactivates TPA and Urokinase. The placenta is an Ephemeral organ present in placental Vertebrates, such as Eutherial Mammals and Sharks during Gestation Cancer procoagulant is a hypothesised Protein, most likely a Cysteine protease Enzyme ( that occurs only in fetal and malignant Factor X, also known by the Eponym Stuart-Prower factor or as thrombokinase, is an Enzyme ( of the coagulation cascade. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled Physiologist Johannes Müller (1801-1858) described fibrin, the substance of a thrombus. Johannes Peter Müller ( July 14, 1801 &ndash April 28, 1858) was a German Physiologist, comparative anatomist Its soluble precursor, fibrinogen, was thus named by Rudolf Virchow (1821-1902), and isolated chemically by Prosper Sylvain Denis (1799-1863). Rudolf Ludwig Karl Virchow ( 13 October 1821 &ndash 5 September 1902) was a German doctor, anthropologist, public health Alexander Schmidt suggested that the conversion from fibrinogen to fibrin was the result of an enzymatic process, and labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin". Alexander Schmidt ( 1831 - April 22, 1894) was a Physiologist who was born on the Island of Mohn which today is called Muhu, Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins [2][3] Arthus discovered in 1890 that calcium was essential in coagulation. Nicolas Maurice Arthus was a French Immunologist and Physiologist. [4][5] Platelets were identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882. Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved Giulio Bizzozero (1846-1901 was an Italian doctor and medical researcher [6]

The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul Morawitz in 1905. Tissue factor, also called thromboplastin, factor III or CD142 is a Protein present in subendothelial tissue, Platelets Paul Oskar Morawitz ( 1879-04-03 in St Petersburg - 1936-07-01) was a German internist and physiologist whose most important [7] At this stage, it was known that thrombokinase/thromboplastin (factor III) was released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), formed thrombin, which converted fibrinogen into fibrin (I). Calcium (Ca2+ plays a vital role in the Anatomy, Physiology and Biochemistry of Organisms and of the cell, particularly [8]

Coagulation factors

The remainder of the biochemical factors in the process of coagulation were largely discovered in the 20th century. The twentieth century of the Common Era began on

A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin (initially and later called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated that its function was the generation of accelerin (Factor VI), which later turned out to be the activated form of V (or Va); hence, VI is not now in active use. [8]

Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups.

Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A; it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to correct hemophilia A. Factor VIII (FVIII is an essential Clotting factor A deficiency of FVIII causes Hemophilia A, a bleeding disorder Haemophilia A (also spelled Hemophilia A or Hæmophilia A) is a Blood clotting disorder caused by a mutation of the Factor VIII gene The 1950s Decade refers to the years of 1950 to 1959 inclusive [8]

Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas (1947-1993). Haemophilia B (also spelled Hemophilia B or Hæmophilia B) is a blood clotting disorder caused by a Mutation of the Factor IX Stephen Christmas ( 12 February, 1947 – 20 December, 1993) was a 5 year old boy when he became the first patient described to have Christmas His deficiency was described by Dr. Rosemary Biggs and Professor R. G. MacFarlane in Oxford, UK. The factor is hence called Christmas Factor or Christmas Eve Factor. Christmas lived in Canada, and campaigned for blood transfusion safety until succumbing to transfusion-related AIDS at age 46. An alternative name for the factor is plasma thromboplastin component, given by an independent group in California. [8]

Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a prolonged bleeding time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in 1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. Factors XI and XIII were identified in 1953 and 1961, respectively. [8]

The view that the coagulation process was a "cascade" or "waterfall" was enunciated almost simultaneously by MacFarlane[9] in the UK and by Davie and Ratnoff[10] in the USA, respectively.

Nomenclature

The usage of Roman numerals rather than eponyms or systematic names was agreed upon during annual conferences (starting in 1955) of hemostasis experts. Roman numerals are a Numeral system originating in ancient Rome, adapted from Etruscan numerals. In 1962, consensus was achieved on the numbering of factors I-XII. [11] This committee evolved into the present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald Factor were given to further coagulation-related proteins, namely prekallikrein and high molecular weight kininogen respectively. Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family High-molecular-weight kininogen ( HMWK) also known as the Williams-Fitzgerald-Flaujeac factor or the Fitzgerald factor or the HMWK-kallikrein factor [8]

Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to consist of ten further factors, and accelerin was found to be activated Factor V.

Other species

All mammals have an extremely closely related blood coagulation process, using a combined cellular and serine protease process. In fact, it is possible for any mammalian coagulation factor to "cleave" its equivalent target in any other mammal. The only nonmammalian animal known to use serine proteases for blood coagulation is the horseshoe crab. The horseshoe crab or Atlantic horseshoe crab ( Limulus polyphemus) is a marine Chelicerate Arthropod.

References

  1. ^ Furie B, Furie BC (2005). "Thrombus formation in vivo". J. Clin. Invest. 115 (12): 3355-62. doi:10.1172/JCI26987. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16322780.   Full text at PMC: 1297262
  2. ^ Schmidt A (1872). PubMed Central is a free digital database of full-text Scientific literature in biomedical and life sciences "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413-538.  
  3. ^ Schmidt A. Zur Blutlehre. Leipzig: Vogel, 1892.
  4. ^ Arthus M, Pagès C (1890). "Nouvelle theorie chimique de la coagulation du sang". Arch Physiol Norm Pathol 5: 739–46.  
  5. ^ Shapiro SS (2003). "Treating thrombosis in the 21st century". N. Engl. J. Med. 349 (18): 1762–4. doi:10.1056/NEJMe038152. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14585945.  
  6. ^ Brewer DB (2006). "Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet". Br. J. Haematol. 133 (3): 251–8. doi:10.1111/j.1365-2141.2006.06036.x. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16643426.  
  7. ^ Morawitz P (1905). "Die Chemie der Blutgerinnung". Ergebn Physiol 4: 307-422.  
  8. ^ a b c d e f Giangrande PL (2003). "Six characters in search of an author: the history of the nomenclature of coagulation factors". Br. J. Haematol. 121 (5): 703–12. doi:10.1046/j.1365-2141.2003.04333.x. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12780784.  
  9. ^ MacFarlane RG (1964). "An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier". Nature 202: 498–9. doi::10.1038/202498a0. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14167839.  
  10. ^ Davie EW, Ratnoff OD (1964). "Waterfall sequence for intrinsic blood clotting". Science 145: 1310–2. doi:10.1126/science.145.3638.1310. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14173416.  
  11. ^ Wright IS (1962). "The nomenclature of blood clotting factors". Can Med Assoc J 86: 373–4. PMID 14008442.   Full text at PMC: 1848865

External links

3D structures

PubMed Central is a free digital database of full-text Scientific literature in biomedical and life sciences Orientations of Proteins in Membranes (OPM database provides spatial positions of protein three-dimensional structures with respect to the Lipid bilayer. Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA domain is a Protein domain that contains post-translational modifications ofmany glutamate residues by Orientations of Proteins in Membranes (OPM database provides spatial positions of protein three-dimensional structures with respect to the Lipid bilayer. Discoidin domain (also known as F5/8 type C domain or C2-like domain is major domain of many Blood coagulation factors.

Dictionary

coagulation

-noun

  1. the process by which blood forms solid clots
  2. similar solidification of other materials (e.g. of tofu).
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